A major hurdle in the development of many pharmaceutically active drugs is to find an appropriate delivery form for their administration in a subject to achieve a therapeutic level at the site of action. Additionally, if the target of the drug is a specific organ or a localized tumor, systemic administration may not be sufficient to reach effective drug concentrations at the target site to achieve the desired therapeutic effect. For example, many oligonucleotides or proteins, often of large molecular weights (for example, antibodies, hormones etc.), are found to be efficient drugs in vitro, but it is often problematic to reach an effective concentration of the drug at their in vivo target to illicit a therapeutic effect.
Another hurdle to overcome in administering drugs to a subject is crossing the blood-brain barrier. The blood brain barrier is very often an impenetrable obstacle for substances to cross even when the substances are administered intravenously. Difficulties in penetrating the blood-brain barrier can be traced to many causes, including, for example, a particular drug's chemical stability characteristics, its molecular weight, and/or its chemical charge and polarity etc.
Other drugs have toxic effects and therefore should only be administered locally. In the same context, imaging substances for example may best be suited for local administration to minimize systemic toxic side effects and/or improve their performance.
Existing techniques for regional drug delivery, such as impregnated polymer discs or bolus injections, depend on physical diffusion to distribute the agent. Often the distribution of large molecules is restricted and the rate of distribution is inversely related to the size of the agent and is slow relatively to tissue clearance. But even drugs with ideal characteristics for diffusion very often attain little satisfactory concentrations in the margins of the tissue or the tumor. In the case of lethal tumors, cell populations that exist beyond the site of drug delivery escape exposure to the drug because of inhomogeneous infusion determined to the concentration gradient that develops between the site of injection and the advancing tumor border.
For convection enhanced delivery of drugs into brain tissue a highly sophisticated delivery system has been described, see for example, PCT publication WO 95/05864. Substances are administered with a specific flow into a tissue or a tumor (for example, 0.5 to 15.0 μL/min) and the concentration of the drug spreads homogeneously around the infusion site. This convection enhanced delivery technique has only been possible with huge and heavy syringe pumps since the demand towards the continuity of flow characteristics is very high. The syringe pumps are described as being connected directly with the catheter which is positioned into the brain. Portable pumps used for the application of drugs into the vein, the interstitium or intraspinal applications have been regarded to have insufficient flow characteristics for this use. Also, a catheter directly accessing the target tissue can be used only during clinical treatment, but has to be renewed after some time (hours or days, for example) because the entrance has the potential to become infected.
The necessity for huge, non-portable syringe pumps and its direct combination with the catheter for implantation into the brain has restricted the use of this application system to in-patient treatment only. In particular, it is very inconvenient for the subject when the catheter is exposed or visible outside the body (for example, the head) during out-patient treatment. Beside this cosmetic disadvantage for the subject, the exposed catheter brings an additional risk of infection as the site of entry can be easily manipulated by mechanic strain. Furthermore, repeated surgery for implantation of a new catheter is desired in interval therapy. These surgeries are additional psychological obstacles as well, and involve a high risk of an additional infection and further complications for the subject.
The administration of drugs especially to the brain by indwelling pumps has also been describe in context with the treatment of movement disorders, see for example, U.S. Pat. No. 5,711,316, or with neurodegenerative disorders, see for example, U.S. Pat. No. 5,735,814. Whereas the technique of these apparatus is highly sophisticated, comprising a sensor as well, it would not fit the demands of convection enhanced delivery administration into a brain tumor. For example, these pumps have insufficient flow characteristics to be used in this application. Additionally, in the administration of fluids over a long period of time (for example, days, weeks or months) the electric supply of the pump will likely require recharging or replacement leading to further surgical intervention. Furthermore, for interval treatment in combination with huge volumes of solvents the supply of these solvents has to be extra-corporal or else otherwise additional surgeries would be necessary.
The administration of substances periodically via a access port system that can be connected with a catheter has also been described, see for example, U.S. Pat. No. 5,897,528. Access ports are in general chambers covered with a septum, which enables repeated puncture with a needle. The access port is connected via a access port catheter and a connector with an infusion catheter. This system allows repeated administration of pharmaceutical fluids. The positioning of the catheter during periodic administration of drugs as so far described, is restricted to body fluids (for example, interstitial fluids) because by implanting the catheter into a tumor or tissue, the openings of the catheter become overgrown with cells, especially tumor cells, when located herein and closed thereby during the time no solvent is administered.
Therefore, there remains a need for the administration of a therapeutic agent to a subject with continuous flow by employing convection enhanced delivery technique during out-patient treatment that is suitable for interval therapy, minimizes the number of surgeries needed for implantation and maintenance, is convenient to handle and/or is comfortable to wear during use. A faster onset of action, improved side-effect profile, enhanced stability, reduced dosing amount and frequency, and improved patient compliance are also desired for the delivery of therapeutic agents to a subject. In addition, it would be much desired to have a system having an indwelling pump and a catheter that can be located intrathecally. The discussion that follows discloses delivery systems, kits, and methods that help to fulfill these needs.